Bivalent COVID-19 booster vaccines and the absence of BA.5-specific antibodies
Authors: Juan Manuel Carreño, Gagandeep Singh, Viviana Simon, Florian Krammer
Journal: The Lancet Microbe (2023)

Vaccination against COVID-19 increased immunity in the population, which reduced viral transmission and protected against severe disease. However, continuous emergence of SARS-CoV-2 variants required the implementation of bivalent boosters including the wild-type (D614G) and omicron (BA.5) spike. Improved effectiveness of the bivalent booster versus monovalent booster against omicron subvariants has been reported;1Lin DY Xu Y Gu Y et al.Effectiveness of bivalent boosters against severe omicron infection.N Engl J Med. 2023; 388: 764-766Crossref PubMed Scopus (21) Google Scholar however, few differences in the immune response have been detected.2Kurhade C Zou J Xia H et al.Low neutralization of SARS-CoV-2 omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster.Nat Med. 2023; 29: 344-347Crossref PubMed Scopus (99) Google Scholar, 3Wang Q Bowen A Valdez R et al.Antibody response to omicron BA.4-BA.5 bivalent booster.N Engl J Med. 2023; 388: 567-569Crossref PubMed Scopus (35) Google Scholar We investigated whether a bivalent COVID-19 booster vaccine that included wild-type spike and BA.5 spike induced detectable BA.5-specific antibody responses in serum. 16 serum samples collected at mean 31 days (SD 63 [range 0–260]) before and a mean 16 days (8 [6–31]) after receiving the bivalent booster were tested for antibody binding and avidity to the receptor binding domain (RBD) of wild-type and BA.5 SARS-CoV-2. Neutralisation of wild-type and BA.5 viruses was determined. Omicron-specific antibodies were measured by depletion of wild-type RBD reactive antibodies and assessment of depleted serum samples against BA.5 RBD. A substantial increase in antibody binding to wild-type and BA.5 RBD as well as in neutralisation of wild-type and BA.5 viruses was seen in serum samples after receiving the bivalent booster (figure, appendix p 6). There were substantial differences in binding of post-booster serum samples between wild-type and BA.5 RBDs; however, differences in neutralisation were not significant. Pre-booster and post-booster RBD antibody avidity was lower against BA.5 RBD than wild-type RBD, which prompted us to look for BA.5 specific antibodies. Wild-type RBD depleted serum samples had undetectable reactivity to wild-type RBD—as expected—and to BA.5 RBD, suggesting that a single exposure to BA.5 antigens by the administration of bivalent vaccine boosters does not elicit robust concentrations of BA.5 specific serum antibodies. Reduced sensitivity of antibody tests based on wild-type viral antigens was detected in previously SARS-CoV-2 antigen naive individuals after omicron infection.4Rössler A Knabl L Raschbichler LM et al.Reduced sensitivity of antibody tests after omicron infection.Lancet Microbe. 2023; 4: e10-e11Summary Full Text Full Text PDF PubMed Scopus (6) Google Scholar However, most of the global population has been infected with ancestral strains or exposed to wild-type antigens through vaccination, hence our results are relevant for the current immune status of the population worldwide. Moreover, our data align with results from April, 2023, which indicate that a monovalent booster with BA.1 vaccine elicits robust spike-specific germinal centre B-cell responses but very low numbers of de-novo B cells targeting variant-specific epitopes.5Alsoussi WB Malladi SK Zhou JQ et al.SARS-CoV-2 omicron boosting induces de novo B cell response in humans.Nature. 2023; (published online April 3.)https://doi.org/10.1038/s41586-023-06025-4Crossref PubMed Scopus (9) Google Scholar Whether further exposures to omicron antigens will boost these responses to make them detectable in serum remains to be explored. Importantly, it is probable that cross-reactive antibodies towards omicron-antigens contribute to protection. FK and VS are named on SARS-CoV-2-related patent applications as co-inventors (US application serial numbers 17/913 783 and 17/922 777). FK has consulted for Merck and Pfizer, and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures, and Avimex. FK is a co-founder and scientific advisory board member of CastleVax. FK's laboratory is also currently collaborating with Pfizer on animal models for SARS-CoV-2. Download .pdf (.68 MB) Help with pdf files Supplementary appendix Correction to Lancet Microbe 2023; published online May 1. https://doi.org/10.1016/S2666-5247(23)00118-0Carreño JM, Singh G, Simon V, Krammer F, PVI study group. Bivalent COVID-19 booster vaccines and the absence of BA.5-specific antibodies. Lancet Microbe 2023; published online May 1. https://doi.org/10.1016/S2666-5247(23)00118-0— In this Correspondence a figure was erroneously removed from the appendix during processing. The figure has now been readded. This correction has been made as of May 31, 2023. Full-Text PDF Open Access